Cystic fibrosis (CF) is one of the most frequent recessive genetic diseases in the western world caused by mutations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). More than 2,000 different mutations of the CFTR gene have been identified to date, however only a few dozen variants are of known clinical significance with ΔF508 occurring in about 70% of CF patients in North America. Mutations in the CFTR gene can lead to protein deficiency and/or loss in chloride transport function causing the formation of thick mucous at tissue surfaces. There is great clinical heterogeneity in the expression of CF that can include progressive respiratory failure, recurrent lung infections, pancreatic insufficiency, and failure to thrive, that reduces overall life expectancy. Recent evidence supports the benefits of universal CF screening of neonates (before 2 months of age), since early nutritional supplementation contributes to fewer hospitalizations, lower rates of complications with improved physical and cognitive development in children. CF patients diagnosed by newborn screening are associated with better lung function, improved nutritional status and longer survival relative to non-screened subjects. For these reasons, CF is now included within a panel of genetic diseases in newborn screening programs for pre-symptomatic diagnosis of infants at an earlier onset that results in positive clinical outcomes and lower healthcare expenditures.
A “two-tiered” approach is currently used for population-based CF screening using an algorithm based on elevated immunoreactive trypsinogen (IRT) followed by a DNA mutation panel (Parad et al. J. Pediatrics 2005, 147: 878), however the exact IRT threshold and total number of CFTR mutations used varies by jurisdiction (Massie et al. Med. J Australia 2012, 196: 67). Limitations of this primary screening strategy include a high rate of false positives (≈85-90%) as confirmed by low chloride sweat test results (<30 mM), the identification of carriers with CFTR allele variants who do not express the disease, and potential false-negatives for individuals with rare CFTR mutations within diverse populations (Castellani et al. Curr. Opin. Pulmon. Med. 2010, 16: 584). Furthermore, ethical concerns are related to asymptomatic carrier identification that increases costs due to referrals for diagnostic testing, genetic counseling and follow-up patient monitoring. As a result, the pilocarpine-stimulated iontophoresis sweat test remains the “gold standard” for confirmatory diagnosis of CF based on functional assessment of residual CFTR activity in terms of chloride absorptivity from skin. Since IRT and/or mutation screens provide only probable or inconclusive information regarding disease status, only 10-15% of screen-positive CF infants have elevated sweat chloride (>60 mM) with the majority of patients having low/normal chloride (<29 mM) or borderline chloride (30-59 mM). The latter outcome corresponds to an ambiguous diagnostic test result with mild/late-onset phenotypes and poorly understood natural clinical histories requiring repeat sweat testing and on-going clinical assessment.
Thus, there is a need for an improved method for the screening and diagnosis of cystic fibrosis in affected individuals which overcomes at least one of the disadvantages of prior methods.